tbuckley/cabot-search huggingface dataset:
Universal redirection of CAR T cells against solid tumours via membrane-inserted ligands for the CAR
Authors: Angela Q. Zhang, Alexander Hostetler, Laura E. Chen, Vainavi Mukkamala, Wuhbet Abraham, Lucia T. Padilla, Alexandra N. Wolff, Laura Maiorino, Coralie M. Backlund, Aereas Aung, Mariane Melo, Na Li, Shengwei Wu, Darrell J. Irvine
Journal: Nature Biomedical Engineering (2023)

The effectiveness of chimaeric antigen receptor (CAR) T cell therapies for solid tumours is hindered by difficulties in the selection of an effective target antigen, owing to the heterogeneous expression of tumour antigens and to target antigen expression in healthy tissues. Here we show that T cells with a CAR specific for fluorescein isothiocyanate (FITC) can be directed against solid tumours via the intratumoural administration of a FITC-conjugated lipid-poly(ethylene)-glycol amphiphile that inserts itself into cell membranes. In syngeneic and human tumour xenografts in mice, 'amphiphile tagging' of tumour cells drove tumour regression via the proliferation and accumulation of FITC-specific CAR T cells in the tumours. In syngeneic tumours, the therapy induced the infiltration of host T cells, elicited endogenous tumour-specific T cell priming and led to activity against distal untreated tumours and to protection against tumour rechallenge. Membrane-inserting ligands for specific CARs may facilitate the development of adoptive cell therapies that work independently of antigen expression and of tissue of origin.
AB1223 WHAT ABOUT BONE MINERAL DENSITY IN RHEUMATOID ARTHRITIS PATIENTS USING GLUCOCORTICOIDS?
Authors: A. Dghaies, K. Maatallah, H. Ferjani, D. Ben Nessib, D. Kaffel, W. Hamdi
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Osteoporosis is a major co-morbidity to screen for in patients with RA. Inflammation, low activity level, and treatments, particularly glucocorticoids, increase the risk of osteoporosis in RA patients and expose them to a high fracture risk. Few studies examined glucocorticoid-induced osteoporosis in patients with RA, especially in Africa. <h3>Objectives</h3> Our study aimed to compare the densitometric profile of RA patients receiving glucocorticoids with that of patients not receiving glucocorticoids, and to assess the fracture risk by the FRAX. <h3>Methods</h3> We conducted a retrospective observational study including patients with RA according to the ACR EULAR criteria in the rheumatology department of Kassab Institute of orthopaedics. General data, demographics, inflammation markers (sedimentation rate (SR) and C reactive protein (CRP)), and disease activity (DAS28 (CRP)) were collected. We compared the parameters of bone mineral density (BMD) and FRAX score for two groups: G1 patients who received glucocorticoids and G2 patients who did not. <h3>Results</h3> A total of 207 patients with RA (169 women and 38 men) were included. The mean age was 57±12.2 years [29-85]. The mean duration of disease progression was 7.1±7 years [0-41]. Sixty percent of RA patients had positive RF and/or ACPA. Obesity was noted in 34% of cases. The mean SR and CRP were 47.6±27mm, and 21.5±28mg/l, respectively. The mean DAS28 (CRP) was 6.23±4.49. Seventy percent of the patients (n=144) were using systemic corticosteroid therapy with a mean dose of 6.26mg±4.5 [0-15] prednisone equivalent with a mean duration of corticosteroid use of 14 months ±4.5. Forty-two percent of the patients had osteoporosis (T score≤ -2,5 DS), 37% had osteopenia (-2,5 DS &lt;T score≤-1 DS), and 18% had normal BMD (T score&gt;-1 DS). The Table 1 summarizes BMD parameters and Frax score in the two groups. <h3>Conclusion</h3> Patients receiving glucocorticoids had a lower bone density, T-score, and a higher fracture risk. Osteoporosis and the high incidence of osteoporotic fractures are dramatic consequences of glucocorticoid therapy in RA patients, leading to marked impairment of their quality of life. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production
Authors: Xilin Wu, Elena A. B. Azizan, Emily Goodchild, Sumedha Garg, Man Hagiyama, Claudia P. Cabrera, Fabio L. Fernandes-Rosa, Sheerazed Boulkroun, Jyn Ling Kuan, Zenia Tiang, Alessia David, Masanori Murakami, Charles A. Mein, Eva Wozniak, Wanfeng Zhao, Alison Marker, Folma Buss, Rebecca S. Saleeb, Jackie Salsbury, Yuta Tezuka, Fumitoshi Satoh, Kenji Oki, Aaron M. Udager, Debbie L. Cohen, Heather Wachtel, Peter J. King, William M. Drake, Mark Gurnell, Jiri Ceral, Ales Ryska, Muaatamarulain Mustangin, Yin Ping Wong, Geok Chin Tan, Miroslav Solar, Martin Reincke, William E. Rainey, Roger S. Foo, Yutaka Takaoka, Sandra A. Murray, Maria-Christina Zennaro, Felix Beuschlein, Akihiko Ito, Morris J. Brown
Journal: Nature Genetics (2023)

Abstract Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1 . Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.
Partial breast irradiation compared with whole breast irradiation: a systematic review and meta-analysis
Authors: Dean A Shumway, Kimberly S Corbin, Magdoleen H Farah, Kelly E Viola, Tarek Nayfeh, Samer Saadi, Vishal Shah, Bashar Hasan, Sahrish Shah, Khaled Mohammed, Irbaz Bin Riaz, Larry J Prokop, M Hassan Murad, Zhen Wang
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Early-stage breast cancer is among the most common cancer diagnoses. Adjuvant radiotherapy is an essential component of breast-conserving therapy, and several options exist for tailoring its extent and duration. This study assesses the comparative effectiveness of partial-breast irradiation (PBI) compared with whole-breast irradiation (WBI). Methods A systematic review was completed to identify relevant randomized clinical trials and comparative observational studies. Independent reviewers working in pairs selected studies and extracted data. Randomized trial results were pooled using a random effects model. Prespecified main outcomes were ipsilateral breast recurrence (IBR), cosmesis, and adverse events (AEs). Results Fourteen randomized clinical trials and 6 comparative observational studies with 17 234 patients evaluated the comparative effectiveness of PBI. PBI was not statistically significantly different from WBI for IBR at 5 years (RR = 1.34, 95% CI = 0.83 to 2.18; high strength of evidence [SOE]) and 10 years (RR = 1.29, 95% CI = 0.87 to 1.91; high SOE). Evidence for cosmetic outcomes was insufficient. Statistically significantly fewer acute AEs were reported with PBI compared with WBI, with no statistically significant difference in late AEs. Data from subgroups according to patient, tumor, and treatment characteristics were insufficient. Intraoperative radiotherapy was associated with higher IBR at 5, 10, and over than 10 years (high SOE) compared with WBI. Conclusions Ipsilateral breast recurrence was not statistically significantly different between PBI and WBI. Acute AEs were less frequent with PBI. This evidence supports the effectiveness of PBI among selected patients with early-stage, favorable-risk breast cancer who are similar to those represented in the included studies.
Targeting lymphoid-derived IL-17 signaling to delay skin aging
Authors: Paloma Solá, Elisabetta Mereu, Júlia Bonjoch, Marta Casado-Peláez, Neus Prats, Mònica Aguilera, Oscar Reina, Enrique Blanco, Manel Esteller, Luciano Di Croce, Holger Heyn, Guiomar Solanas, Salvador Aznar Benitah
Journal: Nature Aging (2023)

Abstract Skin aging is characterized by structural and functional changes that contribute to age-associated frailty. This probably depends on synergy between alterations in the local niche and stem cell-intrinsic changes, underscored by proinflammatory microenvironments that drive pleotropic changes. The nature of these age-associated inflammatory cues, or how they affect tissue aging, is unknown. Based on single-cell RNA sequencing of the dermal compartment of mouse skin, we show a skew towards an IL-17-expressing phenotype of T helper cells, γδ T cells and innate lymphoid cells in aged skin. Importantly, in vivo blockade of IL-17 signaling during aging reduces the proinflammatory state of the skin, delaying the appearance of age-related traits. Mechanistically, aberrant IL-17 signals through NF-κB in epidermal cells to impair homeostatic functions while promoting an inflammatory state. Our results indicate that aged skin shows signs of chronic inflammation and that increased IL-17 signaling could be targeted to prevent age-associated skin ailments.
Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury
Authors: Kerri D. Pryce, Randal A. Serafini, Aarthi Ramakrishnan, Andrew Nicolais, Ilinca M. Giosan, Claire Polizu, Angélica Torres-Berrío, Sreeya Vuppala, Hope Kronman, Anne Ruiz, Sevasti Gaspari, Catherine J. Peña, Farhana Sakloth, Vasiliki Mitsi, John van Duzer, Ralph Mazitschek, Matthew Jarpe, Li Shen, Eric J. Nestler, Venetia Zachariou
Journal: Nature Neuroscience (2023)
Phospholipid scramblase-1 regulates innate type 2 inflammation in mouse lungs via CRTH2-dependent mechanisms
Authors: Ashley Hernandez-Gutierrez, Sonoor Majid, Adam Eberle, Ashley Choi, Parand Sorkhdini, Dongqin Yang, Alina Xiaoyu Yang, Carmelissa Norbrun, Chuan Hua He, Chang-min Lee, Chun Geun Lee, Jack A. Elias, Yang Zhou
Journal: Journal of Clinical Investigation (2023)

Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies have highlighted the importance of innate type 2 immune responses and innate lymphoid 2 cells (ILC2s) in these disorders. However, the mechanisms that control the development of pulmonary innate type 2 responses (IT2IR) and the recruitment and/or activation of ILC2 cells are poorly understood. In mouse models of pulmonary IT2IR, we demonstrated that phospholipid scramblase-1 (PLSCR1), a type II transmembrane protein that mediates bidirectional and nonspecific translocation of phospholipids between the inner and outer leaflets of the plasma membrane, was a critical regulator of IT2IR in the lung. We further suggested that (a) PLSCR1 bound to and physically interacted with chemoattractant receptor-homologous molecule(CRTH2), which is a G-protein-coupled receptor that is expressed on TH2 cells and on multiple immune cells and is commonly used to identify ILC2 cells, and (b) the effects of PLSCR1 on ILC2 activation and IT2IR were mediated via CRTH2-dependent mechanisms. Overall, our studies demonstrated that PLSCR1 played an essential role in the pathogenesis of ILC2 responses, providing critical insights into biology and disease pathogenesis and identifying targets that can be manipulated in attempts to control IT2IR in chronic diseases such as asthma.
An integrated cell atlas of the lung in health and disease
Authors: Lisa Sikkema, Ciro Ramírez-Suástegui, Daniel C. Strobl, Tessa E. Gillett, Luke Zappia, Elo Madissoon, Nikolay S. Markov, Laure-Emmanuelle Zaragosi, Yuge Ji, Meshal Ansari, Marie-Jeanne Arguel, Leonie Apperloo, Martin Banchero, Christophe Bécavin, Marijn Berg, Evgeny Chichelnitskiy, Mei-i Chung, Antoine Collin, Aurore C. A. Gay, Janine Gote-Schniering, Baharak Hooshiar Kashani, Kemal Inecik, Manu Jain, Theodore S. Kapellos, Tessa M. Kole, Sylvie Leroy, Christoph H. Mayr, Amanda J. Oliver, Michael von Papen, Lance Peter, Chase J. Taylor, Thomas Walzthoeni, Chuan Xu, Linh T. Bui, Carlo De Donno, Leander Dony, Alen Faiz, Minzhe Guo, Austin J. Gutierrez, Lukas Heumos, Ni Huang, Ignacio L. Ibarra, Nathan D. Jackson, Preetish Kadur Lakshminarasimha Murthy, Mohammad Lotfollahi, Tracy Tabib, Carlos Talavera-López, Kyle J. Travaglini, Anna Wilbrey-Clark, Kaylee B. Worlock, Masahiro Yoshida, Yuexin Chen, James S. Hagood, Ahmed Agami, Peter Horvath, Joakim Lundeberg, Charles-Hugo Marquette, Gloria Pryhuber, Chistos Samakovlis, Xin Sun, Lorraine B. Ware, Kun Zhang, Maarten van den Berge, Yohan Bossé, Tushar J. Desai, Oliver Eickelberg, Naftali Kaminski, Mark A. Krasnow, Robert Lafyatis, Marko Z. Nikolic, Joseph E. Powell, Jayaraj Rajagopal, Mauricio Rojas, Orit Rozenblatt-Rosen, Max A. Seibold, Dean Sheppard, Douglas P. Shepherd, Don D. Sin, Wim Timens, Alexander M. Tsankov, Jeffrey Whitsett, Yan Xu, Nicholas E. Banovich, Pascal Barbry, Thu Elizabeth Duong, Christine S. Falk, Kerstin B. Meyer, Jonathan A. Kropski, Dana Pe’er, Herbert B. Schiller, Purushothama Rao Tata, Joachim L. Schultze, Sara A. Teichmann, Alexander V. Misharin, Martijn C. Nawijn, Malte D. Luecken, Fabian J. Theis
Journal: Nature Medicine (2023)

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1
Defining blood-induced microglia functions in neurodegeneration through multiomic profiling
Authors: Andrew S. Mendiola, Zhaoqi Yan, Karuna Dixit, Jeffrey R. Johnson, Mehdi Bouhaddou, Anke Meyer-Franke, Min-Gyoung Shin, Yu Yong, Ayushi Agrawal, Eilidh MacDonald, Gayathri Muthukumar, Clairice Pearce, Nikhita Arun, Belinda Cabriga, Rosa Meza-Acevedo, Maria del Pilar S. Alzamora, Scott S. Zamvil, Alexander R. Pico, Jae Kyu Ryu, Nevan J. Krogan, Katerina Akassoglou
Journal: Nature Immunology (2023)

Abstract Blood protein extravasation through a disrupted blood–brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer’s disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.
Tom Nolan’s research reviews—8 June 2023
Authors: Tom Nolan
Journal: BMJ (2023)

How do DOs do?How important are qualifications in modern day healthcare?Regardless of how good you are at your job, whether you're a consultant, staff grade, registrar, nurse specialist, physician's associate, or GP, it still puts you in a pecking order.In the US there's the extra factor of whether doctors have a medical doctor (MD) or doctor of osteopathic medicine (DO) qualification.Allopathic (MD) and osteopathic (DO) physicians can prescribe, operate, and train in primary or secondary care.Those who are trained the osteopathic way learn a whole person approach that considers the connection of body, mind, and spirit in delivering healthcare, and receive osteopathic manipulation training on top of their medical training.There are far fewer DOs than MDs, with less competitive medical school entry requirements, and, when it comes to status, apparently the MDs rule the roost.
Inherited human ezrin deficiency impairs adaptive immunity
Authors: Blanca García-Solís, Ana Van Den Rym, Laura Martinez-Martínez, Teresa Franco, Jareb J. Pérez-Caraballo, Janet Markle, Carolina Cubillos-Zapata, Ana V. Marín, María J. Recio, José R. Regueiro, Alfonso Navarro-Zapata, Carmen Mestre-Durán, Cristina Ferreras, Carla Martín Cotázar, Roció Mena, Carlos de la Calle-Fabregat, Alberto López-Lera, Miguel Fernández Arquero, Antonio Pérez-Martínez, Eduardo López-Collazo, Silvia Sánchez-Ramón, Jean-Laurent Casanova, Rubén Martínez-Barricarte, Oscar de la Calle-Martín, Rebeca Pérez de Diego
Journal: Journal of Allergy and Clinical Immunology (2023)

<h3>Background</h3> Inborn errors of immunity (IEI) are a group of monogenic diseases that confer susceptibility to infection, autoimmunity, and cancer. Despite the life-threatening consequences of some IEI, their genetic cause remains unknown in many patients. <h3>Objective</h3> We investigated a patient with an IEI of unknown genetic etiology. <h3>Methods</h3> Whole-exome sequencing identified a homozygous missense mutation of the gene encoding ezrin <i>(EZR),</i> substituting a threonine for an alanine at position 129. <h3>Results</h3> Ezrin is one of the subunits of the ezrin, radixin, and moesin (ERM) complex. The ERM complex links the plasma membrane to the cytoskeleton and is crucial for the assembly of an efficient immune response. The A129T mutation abolishes basal phosphorylation and decreases calcium signaling, leading to complete loss of function. Consistent with the pleiotropic function of ezrin in myriad immune cells, multidimensional immunophenotyping by mass and flow cytometry revealed that in addition to hypogammaglobulinemia, the patient had low frequencies of switched memory B cells, CD4<sup>+</sup> and CD8<sup>+</sup> T cells, MAIT, γδ T cells, and <sup>central</sup>naive CD4<sup>+</sup> cells. <h3>Conclusions</h3> Autosomal-recessive human ezrin deficiency is a newly recognized genetic cause of B-cell deficiency affecting cellular and humoral immunity.
A Biomimicking and Multiarm Self‐Indicating Nanoassembly for Site‐Specific Photothermal‐Potentiated Thrombolysis Assessed in Microfluidic and In Vivo Models
Authors: Kuan‐Ting Liu, Edgar Daniel Quiñones, Ming‐Hsin Liu, Che‐Wei Lin, Yan‐Ting Chen, Chia‐Che Chiang, Kevin Chia‐Wen Wu, Yu‐Jui Fan, Er‐Yuan Chuang, Jiashing Yu
Journal: Advanced Healthcare Materials (2023)

Thrombolytic and antithrombotic therapies are limited by short circulation time and the risk of off-target hemorrhage. Integrating a thrombus-homing strategy with photothermal therapy are proposed to address these limitations. Using glycol chitosan, polypyrrole, iron oxide and heparin, biomimicking GCPIH nanoparticles are developed for targeted thrombus delivery and thrombolysis. The nanoassembly achieves precise delivery of polypyrrole, exhibiting biocompatibility, selective accumulation at multiple thrombus sites, and enhanced thrombolysis through photothermal activation. To simulate targeted thrombolysis, a microfluidic model predicting thrombolysis dynamics in realistic pathological scenarios is designed. Human blood assessments validate the precise homing of GCPIH nanoparticles to activated thrombus microenvironments. Efficient near-infrared phototherapeutic effects are demonstrated at thrombus lesions under physiological flow conditions ex vivo. The combined investigations provide compelling evidence supporting the potential of GCPIH nanoparticles for effective thrombus therapy. The microfluidic model also offers a platform for advanced thrombolytic nanomedicine development.
Safety Monitoring of mRNA COVID-19 Vaccine Third Doses Among Children Aged 6 Months–5 Years — United States, June 17, 2022–May 7, 2023
Authors: Anne M. Hause, Paige Marquez, Bicheng Zhang, Pedro L. Moro, Tanya R. Myers, Colin Bradley, Samaneh Bazel, Sarada S. Panchanathan, Tom T. Shimabukuro, David K. Shay
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

As of May 7, 2023, CDC's Advisory Committee on Immunization Practices (ACIP) recommends that all children aged 6 months-5 years receive at least 1 age-appropriate bivalent mRNA COVID-19 vaccine dose. Depending on their COVID-19 vaccination history and history of immunocompromise, these children might also need additional doses* (1-3). Initial vaccine safety findings after primary series vaccination among children aged 6 months-5 years showed that transient local and systemic reactions were common whereas serious adverse events were rare (4). To characterize the safety of a third mRNA COVID-19 vaccine dose among children aged 6 months-5 years, CDC reviewed adverse events and health surveys reported to v-safe, a voluntary smartphone-based U.S. safety surveillance system established by CDC to monitor health after COVID-19 vaccination (https://vsafe.cdc.gov/en/) and the Vaccine Adverse Event Reporting System (VAERS), a U.S. passive vaccine safety surveillance system co-managed by CDC and the Food and Drug Administration (FDA) (https://vaers.hhs.gov/) (5). During June 17, 2022-May 7, 2023, approximately 495,576 children aged 6 months-4 years received a third dose (monovalent or bivalent) of Pfizer-BioNTech vaccine and 63,919 children aged 6 months-5 years received a third dose of Moderna vaccine.† A third mRNA COVID-19 vaccination was recorded for 2,969 children in v-safe; approximately 37.7% had no reported reactions, and among those for whom reactions were reported, most reactions were mild and transient. VAERS received 536 reports after a third dose of mRNA COVID-19 vaccine for children in these age groups; 98.5% of reports were nonserious and most (78.4%) were classified as a vaccination error.§ No new safety concerns were identified. Preliminary safety findings after a third dose of COVID-19 vaccine for children aged 6 months-5 years are similar to those after other doses. Health care providers can counsel parents and guardians of young children that most reactions reported after vaccination with Pfizer-BioNTech or Moderna vaccine were mild and transient and that serious adverse events are rare.